Experimental findings demonstrate enhanced efficacy of DNMT1 inhibitors in colon cancer by targeting UHRF1-SUV39H1/H2 crosstalk, suggesting a new therapeutic approach.
Key Points
The research aims to identify mechanisms that limit the effectiveness of DNMT1 inhibitors and to explore potential therapeutic targets to enhance their efficacy in colon cancer cells.
Defined crosstalk mechanism involving UHRF1 and SUV39H1/H2 in colon cancer cells.
Utilized integrative epigenomic profiling and biochemical analyses.
Investigated effects of disrupting UHRF1 function and H3K18ub-recognition motif on histone modifications.
Transient DNA hypomethylation leads to UHRF1-dependent H3K18ub, promoting H3K9me3 deposition.
Disruption of UHRF1 or SUV39H1 recognition prevents H3K9me3 accumulation and augments TSG re-expression.
Enhanced antiproliferative effects of DNMT1 inhibitors were observed in colon cancer cells.